( 2R,6R )-hydroxynorketamine exerts mGlu 2 receptor-dependent antidepressant actions
Panos Zanos, Jaclyn N. Highland, Brent W. Stewart, Polymnia Georgiou, Carleigh E. Jenne, Jacqueline Lovett, Patrick J. Morris, Craig J. Thomas, Ruin Moaddel, Carlos A. Zarate, Todd D Gould
Proceedings of the National Academy of Sciences March 13, 2019 DOI: 10.1073/pnas.1819540116 (opens in new tab) via OpenAlex
Summary
AI-generated from the abstractA single subanesthetic dose of ketamine produces rapid (within hours) and sustained antidepressant effects, unlike standard antidepressants that take months and fail in about 30% of patients. The ketamine metabolite (2R,6R)-hydroxynorketamine [(2R,6R)-HNK] is a rapid-acting antidepressant candidate with fewer adverse effects. Using behavioral, genetic, pharmacological approaches and EEG measurements, the study found that antidepressant-relevant actions of (2R,6R)-HNK involve metabotropic glutamate receptor subtype 2 (mGlu2) signaling and identified high-frequency EEG oscillations as a marker of rapid antidepressant responses. The findings suggest clinical trials combining subtherapeutic doses of mGlu2 receptor inhibitors with ketamine or (2R,6R)-HNK for depression treatment.
Study at a glance
| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Intervention | ketamine |
| Topics | Ketamine |
| Keywords | Antidepressant Metabotropic receptor Pharmacology Metabotropic glutamate receptor |
| Citations | 153 |
| Key finding | The antidepressant-relevant actions of (2R,6R)-HNK converge with mGlu2 receptor signaling, and high-frequency EEG oscillations are a marker associated with rapid antidepressant responses. |
Abstract
Significance Despite available medications for depression, currently approved antidepressants take months to exert therapeutic effects, and ∼30% of patients remain treatment resistant. In contrast, a single subanesthetic dose of ketamine exerts rapid (within hours) and sustained antidepressant actions. Preclinical studies indicate that the ketamine metabolite ( 2R , 6R )-hydroxynorketamine [( 2R , 6R )-HNK] is a rapid-acting antidepressant candidate with limited adverse effects compared with ketamine. Using behavioral, genetic, and pharmacological approaches and EEG measurements, we determined that the mechanism underlying antidepressant-relevant actions of ( 2R , 6R )-HNK converges with metabotropic glutamate receptor subtype 2 (mGlu 2 ) receptor signaling and identified high-frequency EEG oscillations as a marker associated with rapid antidepressant responses. Our data support the use of individually subtherapeutic doses of mGlu 2 receptor inhibitors with ketamine or ( 2R , 6R )-HNK in clinical trials for the treatment of depression.